DE2400218A1 - PHARMACEUTICAL FORMULATIONS - Google Patents

Description

DR. BERG DiPL .-: NG. STAPF PATENT LAWYERS

8 MUNICH SO. MAUERKIRCHERSTR. 4B 2400218

Attorney File 24-644 January 3, 1974

Be / Sch

Wellcome Foundation Ltd. London / England

"Pharmaceutical Formulations"

The present invention relates to chemotherapeutic ones Solutions containing a sulfonamide and a sulfonamide potentiator contain.

Aqueous injectable preparations containing both a sulfonamide as well as a sulfonamide potentiator already manufactured, for which purpose a pharmaceutically

B 251 "-2-

4Q9829 / 1062

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sulfonamide wearable salt with either the sulfonamidpotentiato.r in solution in a water-miscible organic solvent or with the sulfonamide potentiator used in the form of particles as a dispersion. In both cases the p “value of the formulation is strongly basic.

It has been found that when the _pH value at the above solutions, the lower end of the basic scale approaches to neutral p "values that approaches, is insoluble complexes of the sulfonamide and Sulfonamidpotentiators, for example, insoluble complexes of SuIfamethoxazol and Can form trimethoprim. The formation of these complexes makes the preparation unsuitable for injection.

While the injectables mentioned above are valuable, there are certain limits to their use, i.e. that its high ρττ value sometimes causes tissue damage to the Ingektionsstelle can cause and that sometimes haemolysis which can cause blood clot formation in the Veins elsewhere can cause. Furthermore, the complex formation can occur more quickly if the Formulations for slightly acidic or neutral intravenous solutions or drip supplies, e.g. saline solution and dextrose, may be added.

It should be noted that the previous dispersions are not used in every F _n IIe for intravenous (hereinafter "IV"

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2400211

abbreviated.) Administration because of their particulate nature were suitable.

In particular, the conventional I.V. have drip supplies and infusions conventionally have a neutral to slightly acidic p "value, for example saline, and accordingly, if the previous injectable solution is added to this type of infusion solution or drip supply, Insoluble complexes can form before the infusion is fully administered to the patient (conventionally it is desirable that the infusions are carried out on the patient for 8 to 24 hours).

It has also been found that the sterilization of the injectable preparations with basic p "values, for which an autoclave is used for 20 minutes at 121 ° C., (a preferred" sterilization process because of its tolerability) usually causes the sulfonamide in the basic p _H Preparations, for example sulfamethoxazole, are oxidized and the preparation takes on a yellowish discoloration, which would make the injectable drug unacceptable as a pharmaceutical product.

Accordingly, what is needed is a new and improved injectable solution to overcome the limitations of those previously used overcome injectable preparations. The invention described below overcomes these limitations of

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injectable drugs mentioned above in that it enables them to be injected (slowly) directly into the veins without causing blood clot or tissue damage. Furthermore, the solution of this invention is compatible with acidic IV infusions such as saline, dextrose or Ringer's ¹ S solution, so that no precipitation occurs for a long time when these are used with solutions of sufficient volume. The product of this invention can still be administered orally (undiluted or mixed with liquids), which was not possible with the strongly basic solutions of the preparations. In addition to the pharmaceutical compatibility, such strongly basic solutions and preparations tend to cause tissue damage in the digestive system.

The present invention accordingly provides a clear solution for oral or parenteral administration which contains a chemotherapeutic amount of a sulfonamide with bacterial growth inhibiting (antimicrobial) activity in a medically acceptable water-miscible organic solvent and an effective sulfonamide-potentiating amount of a water-soluble pharmaceutically acceptable monoaddition salt of an acid contains a SuIfonamidpotentiators in water, the clear solution has a p _H ~ value in the range 2 to 7

In further aspects, the present invention provides

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Process for the preparation of the above solution, including the sulfonamide, organic solvent, the sulfonamide potentiator mix together with the appropriate amount of salt-forming acid and water and then, if necessary, adjusts the ρ value of the mixture so that it is in the range from 2 to 7, including the proportions of the various components changes or adds pharmaceutically acceptable acid.

In particular, the invention relates to a new and improved clear aqueous injectable solution of a chemotherapeutic, effective amount of a sulfonamide having antibacterial activity or other antimicrobial activity in a medically compatible water-soluble organic solvent and an effective sulfonamide potentiating agent Amount of a water-soluble pharmaceutically acceptable monoaddition salt of an acid of a sulfonamide potentiator in water.

Furthermore, it is preferred that the ingotable solution contains a sufficient amount of pharmaceutically acceptable acid to bring the total solution to an (acidic) Ρτ, value and the formation of an insoluble "sulfonamide - sulfonamide potentiator complex" after or during education. the solution to avoid. The water-soluble pharmaceutical Compatible salts of the sulfonamide potentiator can be the implementation of a sulfonamide potentiator and a pharmaceutical

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- 6 chemically compatible acids are formed.

A pharmaceutically acceptable monoaddition salt of an acid of a sulfonamide potentiator or a monoaddition salt a pharmaceutically acceptable acid and a sulfonamide potentiator is defined herein as a salt that has a mono-protonated sulfonamide potentiator and an anion contains a pharmaceutically acceptable acid. The ρ value of the solution and the pKa of the pharmaceutically acceptable acid and the sulfonamide potentiator are determined by the corresponding ionization states.

It is common knowledge that chemotherapeutic, especially the antibacterial effectiveness of the sulfonamides and certain 2,4-diaminopyrimidines are mutually increased, if these funds are used together. Although this increase is mutual or reciprocal, here are the 2,4-diaminopyrimidines are referred to as sulfonamide potentiators.

Specific pyrimidines and processes for their preparation are described, for example, in the British patents 715 813, 734 801, 875 562, 920 412, 957 797, 1 128 234, 1 133 766, 1 142 654, 1 223 831, 1 223,882, 1 261 455, 684 759, 774-094, 774-095, 913 710, 970 583,

1,084,103, 1,038,102, 1,129,084, U.S. Patents

2 926 166 and 3 021 332 and South African Patent 65/5618.

Sulfonamide potentiators of the ^{type indicated above are 409829/1062 ~ 7} ~

further described in Belgian patents 782 153, 782 154, 774 281 and 789 904.

The invention is not limited to the use of a specific ■ see sulfonamide potentiators limited. However, it is essential that the sulfonamide potentiator delivers pharmaceutically acceptable mono-acid addition salts that are dissolved in water in satisfactory concentrations at physiologically tolerable levels p "values are soluble.

To a significant class of such sulfonamide potentiators, those particularly, in this invention as pharmaceutical compatible monoaddition salts of an acid are suitable, include 2,4-diaminopyrimidines with a substituted benzyl group in the 5-position together with or without one Lower alkyl group in 6-position.

2,4-Diaminopyrimidines with a substituted benzyl group in the 5-position of the following are particularly preferred general formula (I)

(D,

where R ^ is a hydrogen atom or a lower alkyl, for example methyl or ethyl group and R _{2 is} an aryl group,

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such as a phenyl group, substituted by one or more alkoxy groups, such as a lower alkoxy group, such as methoxy, ethoxy or isobutoxy, amino, nitro, halogen, preferably
Chlorine, alkyl group such as lower alkyl group such as methyl,
Ethyl or trifluoromethyl group and hydroxyl groups is substituted, with aryl of the formula (II) being particularly preferred

(II),

wherein one or both radicals R ^ and R ^ hydrogen, halogen, are preferably chlorine atoms, lower alkyl and lower alkoxy groups, in which one or both radicals Rt- and R ^ Halogen atoms, preferably chlorine or bromine atoms, lower alkyl and lower alkoxy groups.

In view of the explanations given above,
defines alkyl and alkoxy groups as those containing 1 to 20 carbon atoms and lower alkyl and
Lower alkoxy groups with a content of 1 to 6 carbon atoms, in particular 1 to 3 carbon atoms, where they contain straight or branched alkyl or alkoxy groups.

A particularly preferred class of 2.4 ~ diamino-5-benzyl-

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pyrimidines are those of the general formula

7 8 Q
wherein the radicals R ', R and R ^ are identical or different and each, independently of one another, can be alkyl or alkoxy groups having 1 to 4 carbon atoms or the radicals R' and R together an alkylenedioxy group having 1 to 4 carbon atoms, such as a Can form methylenedioxy.

Trimethoprim /S.4~Diamino-5-(3-^.5-"^rL ¹¹ IethoxybeH-zyl) -pyrimidin7, Diaveridin /2".4-Diamino-5-(3 " ^Z f-rdimethoxybenzyl) -pyrimidine / ^r , 2,4-diamino-5- (3" ^z J- "6-trimethoxybenzyl) -pyrimidine, ormetoprim, /2.^-diamino-5- (2-methyl-4,5-dimethoxybenzyl ) -pyrimidinTy 2.4-Diamino-5- (3 · 4-dimethoxy-5-bromobenzyl) -pyrimidine and pyrimethamine /^.4~Diamino-5-(4- chlorophenyl) -6-ethylpyrimidine7.

All of these specific compounds are known to have highly potent chemotherapeutic activity have and that they are potentiators of the sulfonamides in the sense described here.

It is believed that the monoaddition salt of an acid

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is formed by the fact that it is the salt in which the acid connected in the 1-position to the nitrogen atom of the pyrimidine part is.

Substances that act as pharmaceutically acceptable acids to form water-soluble pharmaceutically acceptable Monosalts of the sulfonamide potentiator can be used nen are, for example, pharmaceutically acceptable mineral acids such as sulfuric, phosphoric, hydrochloric, hydrobromic, hydriodic acid, as well as pharmaceutically acceptable organic ones Acids such as pharmaceutically acceptable carboxylic acids, preferably with 1 to 20 carbon atoms and in particular 1 to 10 carbon atoms, for example tartaric acid, citric acid, lactic acid, emboxylic acid, salicylic acid, glutamic acid, Glutaric acid, naphthoic acid, acetic acid and ethylenediaminetetraacetic acid and other pharmaceutically acceptable organic acids such as methanesulfonic acid. The one here for Acids used to form the salts or the salts of the sulfonamide potentiator must be stronger acids, i.e. such with a lower pKa than the sulfonamide. In the present Trap, the preferred acid is citric acid because it is readily available and useful in the practice of the invention is suitable or compatible.

The invention is not limited to the use of any specific sulfonamide. However, it is essential that the sulfonamide used is soluble in a medicinal

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nically compatible organic solvent that is miscible in water that the sulfonamide is sufficient in one organic solvent is soluble and that the solutions of the invention have the desired concentrations. It is also important that the sulfonamide remains in solution in the organic solvent that the solutions of the invention have a physiologically acceptable ρ V / ert and that they do not have an insoluble sulfonamide-sulfonamide potentiator complex form.

Examples of sulfonamides with antimicrobial, especially antibacterial activity and therefore suitable for use in this invention are in Remington's Pharmaceutical Sciences, 14th Edition, Mack Publishing Company, Easton, Pennsylvania, 1970 from Philadelphia College of Pharmacy and Science, pp. 1195 "to 1206, which is incorporated herein by reference is taken.

A suitable general formula for a preferred class of sulfonamides for use in the present invention find is that of formula III

Q \ SO ₂ NH Q (III),

wherein Q is a substituted or unsubstituted pyrimidin-2-yl or --4-yl group or a substituted isoxazolyl-

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group is.

Examples of sulfonamides with antimicrobial, for example antibacterial effectiveness used in the present invention can be used and the effect of which is patented in the manner described are for example Sulfadimethoxin /5'-(4- aminobenzenesulfonamido )-2.4-dimethoxypyrimidinj, Sulfadiazine ^ - (4-aminobenzenesulfonamido) pyrimidine /, Sulfadoxine ^ - (4-aminobenzenesulfonamido) -5.6-dimethoxypyrimidine7, Sulfadimethoxin /4-(4~ aminobenzenesulfonamido)-2.6-dimethoxypyrimidine7, Sulfamethoxazole / 5- (4-aminobenzenesulfonamido) -5-methylisoxazole7 » Sulfachinoxaline / 2-sulfonamidoquinoxaline7, Sulfadimidine /2~-(4-AminobenzQlsulfonamido)-4-.6-dimethylpyrimidiii7, SuIfafurazole / ^ - (4-aminobenzenesulfonamido) -3 · ^ -dimethylisoxazole7and SuIfacetamid ^ T-SuIfanilyacetamid7 «

The sulfonamides can expediently be dissolved in a medically acceptable organic water-miscible solvent, preferably by stirring at room temperature. This can easily be done by adding the sulfonamide to the combination of the organic solvent and water with or without the sulfonamide potentiator salt present, or it can mix sulfonamide with the organic solvent and then both can be added to the water with or without the sulfonamide potentiator salt present will. It is preferred to ensure that the p _H ~ value of the solution to which the sulfonamide

or the salt of the sulfonamide potentiator is added, in any order at a volume and sufficient p "value is maintained to prevent the formation of insoluble salts to avoid. In preparing the therapeutic solution of this invention, the salt of the sulfonamide potential can be used for example to the mixture of organic solvent, Water and sulfonamide can be added or it can the salt of the sulfonamide potentiator is formed by that one can add a pharmaceutically acceptable acid to the water with or without the presence of the organic solvent and with or without the presence of the sulfonamide with the addition of the sulfonamide potentiator as the base material.

The final product formed, i.e. the solution of this invention, is precipitate free.

Suitable medically compatible water-miscible organic solvents for dissolving the sulfonamide include polar solvents such as .Ν-Dimethjjjjrlacetamid, polyethylene glycols with average molecular weights of about 190 to 7500 and with a content of 2. To 159 ethylene glycol monomer (CH ₂ CH ₂ O) units, 1.2-propylene glycol, glycerine, hexamethylene glycol, 1.3-butylene glycol, ethanol, diethylacetamide, dimethylacetamide, dimethyl sulfoxide, dimethylformamide, di- (1.2-propylene glycol, glycerine formal (formylaldehyde), polyethylene glycol ether of tetrahydrofurfuryl alcohol and.

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Usually the ratio of sulfonamide to sulfonamide potentiator is which is suitable as a base material for producing a therapeutic effect, in the order of magnitude of 5: 1 (w / w), although ratios between 10: 1 to 0.1: 1 (w / w) are useful and in some cases can it may be desirable to use a ratio as high as 20: 1 to 0.1: 1 (w / w).

According to this invention, the injectable or oral solution contains about $ 15 to $ 60, preferably $ 10 to 50, and most preferably 20 to 40 # water (v / v) and 30 to 90 #, preferably 40 to 80 # and especially 50 to 70 # (v / v) organic solvent (in this context "it should be noted that all percentages in this application Are w / v percentages unless otherwise stated).

The injectable or oral solution also contains 1 to about 40 # and preferably about 10 to 30 # sulfonamide and 1 to 10 $ and preferably 1 to 5 # sulfonamide potentiator, calculated as base material.

The p n value of the solution of this invention is in the range from 2 to 7 »preferably 2 to 6 and especially 4 to 6, with a range of 4.5 to 5.5 being particularly preferred for solutions of trimethoprim and sulfamethoxazole. Of the The p “value is preferably within these ρ limits held that a sufficient amount of pharmaceutical

409829/1062 ~ ¹⁵ ~

table-compatible acid is added, the preferred amount being between 0.5 and 3 _r 5 # - examples of pharmaceutically compatible acids have already been given in this description. · ·

To make the injectable or oral solution certain desirable To impart properties, it may be advantageous to use preservatives, or Lofcal anesthetic components to add other ingredients that increase stability. It should therefore be pointed out that other ingredients do so Long been added, as these additional ingredients do not achieve the desirable properties of the injectable or oral solution.

The amount of the injectable or oral solution of this invention, those injected or orally in a nipple, etc. for the treatment of bacterial infections or even proto-zone infections (provided the selected sulfonamide has this activity) can be administered varies according to the Type of host, its size, age, general health conditions, and the severity and type of infection. Appropriately, about T ml to about 1000 ml of a Solution that ötwa 5 # wt./ToI. Sulfonamide potentiator and about $ 25 w / v Contains sulfonamide, used to treat bacterial Infections such as those caused by Proteus mirabilis or Haemophilus influenzae will.

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The frequency with which the injectable or oral solution of this invention can be administered to a host will vary on the amount of the active medicament present therein and the needs and requirements of the host.

However, under common circumstances up to about 200 mg / kg sulfonamide and up to about 150 mg / kg sulfonamide potentiator (calculated as base material) can be administered in combinations daily in multiple doses. However, it is it should be noted that the ranges mentioned above are in no way critical and that the dosages should be used accordingly can be administered as required by the host.

The product of this invention is primarily intended for parenteral use. However, it can also be used orally be administered undiluted or, for example, with addition to drinking water, milk, fruit juices, etc.

Flavors such as cherry, orange, etc. can be added.

Oral solutions of this invention are particularly useful for treating humans, especially children, and for treatment suitable for poultry with goccidiosis.

The following examples illustrate the invention. It is point out that all temperatures are given in ° C, unless otherwise stated and where

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no temperatures are given, e.g. füg & as Mixing the ingredients or making the salt is room temperature. It can of course be higher or lower Temperatures are used depending on how quickly one wishes to carry out the mixing or the salt formation, as is known to the person skilled in the art. All percentages in of this application are weight / volume percentages unless otherwise stated.

example 1

The following ingredients were used:

Citric acid (anhydrous) 1.2 g

Sulfamethoxazole (SMX) '8.0 g

Trimethoprim (TMP). 1.6 g

Polyethylene glycol 400 50.0 ml

Propylene glycol 40.0 ml

USP alcohol (95 # ethanol) 13.0 ml

Water 17 »0 ml

The citric acid was dissolved in water. The USP alcohol and the propylene glycol were added to the water with stirring. With continued stirring, TMP became the Mixture added. The polyethylene glycol 400 and SMX were added and the mixture was stirred until it was clear. The p n value was 4.6. The solution was made under vacuum a Whatman No. 2 filter paper filtered. Then nitrogen was bubbled through the solution for 30 seconds and this in 5 ml Filled ampoules. The surface above the solution was flushed with nitrogen for 10 seconds. The vials were heat sealed and treated for 20 minutes at 121 ° C in the autoclave

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Example 2

Example 1 was repeated except that 0.1 g of potassium metabisulfite was added to the water after the citric acid. Furthermore, no nitrogen was used. The solution was treated in an autoclave ^{at 121 ° C. for 20 minutes.}

Example 3

The following ingredients were used:

Citric acid (anhydrous) 1.2 g

Sulfamethoxazole 8.0 g

Trimethoprim 1.6 g "

N.N-dimethylacetamide (DMA) 50.0 ml

Water 50.0 ml

The citric acid was dissolved in water. The TMP was added to the solution and stirred until it was clear. The DMA and SMX were then added and the mixture stirred until clear. The p n value of the solution was 4.6. The solution was under vacuum through a Whatman -No. 2 filter paper filtered, then nitrogen was bubbled through the solution for 30 minutes and this was filled into 5 ml ampoules. The area above the solution was flushed with nitrogen for 10 seconds. The ampoules "were heat-sealed and Treated 20 minutes at 121 ° C in the autoclave.

Example 4-

Example 3 was repeated except that 0.6 g of citric acid was used to form a solution with a p n value of 5-6 was used.

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Example 5

The contents of one ampoule (5 ml) of product from Example 3 were drawn up into a syringe and dissolved in 1 liter of 0.9% sodium chloride injected with stirring. No precipitate was found after 16 hours.

Example 6

The procedure used in Example 5 was repeated, except that a solution of 8.60 g sodium chloride and 0.33 S calcium chloride with sufficient water to form of 1 1 solution, commonly referred to as Ringer's solution, was used instead of 0.9 / 3 sodium chloride. It no precipitate was observed within 16 hours.

Example 7

The following ingredients were used:

Citric acid (anhydrous) 1.0 g

Polyethylene glycol 4-00 50.0 ml

USP alcohol (95 # ethanol) 10.0 ml

Propylene glycol 10.0 ml

Sulfamethoxazole 8.0 g '

Trimethoprim 1.6 g

Water 30.0 ml

The citric acid was dissolved in water. The TMP was then added with continuous stirring until dissolution was accomplished. Polyethylene glycol 400, USP alcohol (95 # ethanol), propylene glycol and SI-TX were added to the solution and the mixture stirred until the solids were dissolved. The p _H ~ value was 4.6. The solution was through

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a Whatman No. 2 Filter paper filtered under vacuum, bubbled with nitrogen, filled into 5 ml ampoules, flushed with nitrogen, sealed under heat and treated in an autoclave ^{at 121 ° C. for 20 minutes.}

The same amount of ingredients and procedure were used, except that 0.1 g of potassium metabisulfite was added and the mixture was stirred until a clear solution was obtained. This was filled into 5 ml ampoules, heat-sealed and ^{treated in an autoclave at 121 °} C. for 20 minutes. A discoloration of the batch through which nitrogen was bubbled was found, but not the batch with bisulfite.

Example 8

The following ingredients were used:

Water 40.0 ml

Citric acid (anhydrous) 0.9 g

Trimethoprim 1.6g

Polyethylene glycol 4-000 48.0 g

Propylene glycol 10.0 ml

USP alcohol ($ 95 ethanol) 10.0 ml

Sulfamethoxazole 8.0 g

The citric acid was dissolved in water. The TMP was added with continuous stirring until a clear solution was obtained. The polyethylene glycol was dissolved in the solution. The propylene glycol, TJSp alcohol (95 # ethanol) and SMX were then added and the mixture was stirred until a clear solution was obtained. The p _H ~ value was 5.1. the

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- 21 -

Solution was vacuumed through a Whatman No. 2 filter paper filtered. Half of the batch was sparged with nitrogen, filled into 5 ml ampoules, with nitrogen rinsed, heat-sealed and autoclaved at 121 ° C for 20 minutes.

0.05 S potassium metabisulfite was added to the other half and the mixture stirred until clear. The solution was filled into 5 ml ampoules, heat-sealed and treated in an autoclave ^{at 121 ° C. for 20 minutes.}

Examples 9 and 10 were followed by the method of Example 1 the specified ingredients mixed and 8 g of sulfamethoxazole and 1.6 g of trimethoprim dissolved therein. In Examples 11 and 12, following the procedure of Example 3, those indicated were made Ingredients mixed and 8 g sulfamethoxazole and 1.6 g Trimethoprim dissolved in it. In Examples 13 and 14, following the procedure of Example 8, the specified ingredients were used mixed and 8 g sulfamethoxazole and 1.6 g trimethoprim dissolved in it.

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at What Lemon Poly- N.N-Di- 38 USP ΡγΦ- - - Loading 4.7 game ser + nenic acid ethylene methyl- Alko ■ py- p "mer- 4.9 (water glycol ⁺⁺ acet- get le'n- k- 4.6 free) amide gly— gene 4.6 col 4.6 2 ml 9 15th 1.2 400/30 - 10 45 Ben- 10 40 1.2 400/50 - 10 - cyl- 11 50 1.2 400/10 40 - alcohol 12th 50 0.9 6000 ⁺⁺⁺ / 12 40 - get 13th 50 0.9 400/10 _ became • Further towards against ben

14 50 0.9 4000 ⁺⁺⁺ / 24 30 - - 5.0

The liquids are expressed by the volume in ml, the pesticides by the weight in g

⁺ The first number indicates the polyethylene glycol used, the second the volume in ml (or the weight in g in Examples 13 and 14).

⁺⁺⁺ solids

Example 15

The following ingredients were used:

DMA. 7.5 ml

SuIfacetamide 2.0 g

Citric acid (anhydrous) 0.15 g

Trimethoprim 0.40 g

Water 17.5 ml

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The citric acid was dissolved in the water. The TIiP was added and the mixture stirred until a clear solution received. DMA and sulfacetamide were then added and the mixture was stirred until it was clear »The ρ value of the solution was 4.7 ·

Example 16

The following ingredients were used:

Sulfamethoxazole 2.0 g

Trimethoprim 0, A- g

Water 12.5 ml

DMA 12.5 ml

Glacial acetic acid 0.1 ml

The glacial acetic acid and DMA were added to water and mixed. The TMP was added and the mixture stirred until clear. SIiX was added and the mixture until formed stirred a clear solution. The ρ value of the solution was 5.8. ·

Example 17

The following ingredients were used:

Water 15.0 ml citric acid (anhydrous) 0.03 g

Trimethoprim 0.03 S

Polyethylene Glycol 1000 7.5 S

Sulfamethoxazole 0.125 g

The citric acid was dissolved in water, trimethoprim added and the mixture stirred until clear. Polyethylene

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glycol and sulfamethoxazole were added and the mixture stirred until it was clear. The p ^ value of the injectable solution was 4.0.

Examples 18-21

Example 1 was repeated except that the following pyrimidines were used as the sulfonamide potentiator instead of trimethoprim were used: 2.4-Diamino-5- (3.4-methylenedioxy-5-methoxybenzyl) pyrimidine, 2,4-diamino-5- (5 · 5-diethyl-4-methoxybenzyl) pyrimidine, 2,4-diamino-5- (5 · 5-dimethoxy-4-methylbenzyl) pyrimidine and 2,4-diamino-5- (3 «4.5-diethylbenzyl) pyrimidine.

Example 22

The following ingredients were used:

USP alcohol (95 # ethanol) citric acid, anhydrous liquid sucrose polyethylene glycol 400 potassium metabisulphite sodium saccharin suIfamethoxaz oil
Trimethoprim
Flavors soluble water purified, qs on

The citric acid, sodium saccharin and potassium metabisulphite were dissolved in water. Polyethylene glycol 400 was then dissolved in the solution and the liquid sucrose, alcohol and soluble flavors added with stirring. That

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9.0 ml 0.9 G 10.0 ml 46.0 ml 0.1 6th 0.1 S. 8.0 S. 1.6 S. q.s. 100.0 ml

Trimethoprim was added and stirred until dissolved. Then sulfamethoxazole was added and that The mixture was stirred until a clear solution was obtained which was suitable for oral administration. As suitable soluble Flavors can either be natural flavors, for example sweet lime, orange or artificial flavors, for example cherry, raspberry, etc. can be used.

Examples 23 and 24

Following the procedure of Example 22 were for oral administration suitable solutions prepared with the following ingredients:

example 23 G Example 24 USP alcohol (95 # ethanol) 5.0 ml Citric acid, anhydrous 0.9 0.9 g Flavors, soluble q.s. ml q.s. glycerin - - S. 10.0 ml Liquid sucrose 10.0 G 10.0 ml Polyethylene glycol 4000 60.0 S. 48.0 g Sulfamethoxazole 8.0 ml 8.0 g Trimethoprim 1.6 ml 1.6 g Purified water 30.0 • 35.0 ml 100.0 100.0 ml

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-Patent claims-

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Claims (1)

- 26 patent claim e: 1. Clear solution for oral or parenteral administration, characterized in that it contains a chemotherapeutic amount of a sulfonamide with antimicrobial "bieller Activity in a medically compatible water-miscible organic solvent and an effective sulfonamide potentiating agent Amount of a water-soluble, pharmaceutically acceptable monoaddition salt of an acid with contains a sulfonamide potentiator in water, the clear solution having a p ^ value in the range from 2 to 7. 2. Clear solution according to claim 1, characterized that the sulfonamide potentiator is 2,4-diamino-5-benzylpyrimidine. 3 · Clear solution according to claim 2, characterized in that the 2,4-diamino-5-benzylpyrimidine the general formula below in which the radicals R ^, R and r "are identical or different and each alkyl or alkoxy group with 1 to -27- 4 0 9 8 2 9/1062 1-400218 7 8 4 carbon atoms or the radicals R 'and R together form an alkylenedioxy group having 1 to 4 carbon atoms such as a methylenedioxy group. 4. Clear solution according to claim 3, characterized that the sulfonamide potentiator is 2.4-mamino-5- (3.4.5-trimethoxybenzyl) -pyrimidine. 5 · Clear solution according to one of claims 1 to 4, characterized in that the salt des Sulfonamide potentiator which is citrate. 6. Clear solution according to one of claims 1 to 5 »characterized in that the sulfonamide the general formula (III) SO ₂ -NH-Q (III) wherein Q is a substituted or unsubstituted pyrimidin-2-yl or -4-yl group or a substituted one Is isoxazolyl group. 7- Clear solution according to claim 6, characterized in that that the sulfonamide sulfamethoxazole is. 8. Clear solution according to one of claims 1 to 7, since 409829/1062 ~ ²⁸ ~. characterized by, ^ _a ß _s i _{e has} a ρ value in the range from 4 to 6 « 9. Clear solution according to claim 8, characterized that it has a ρ value in the range of 4-.5 to 5.5. 10. Clear solution according to claim 1 to 9, characterized in that the clear solution continues contains a pharmaceutically acceptable acid. 11 »Clear solution according to claim 10, characterized in that the pharmaceutically acceptable Acid in an amount of 0.5 to 5> 5 wt * ^, based based on the weight of the solution. 12 «Clear solution according to claim 1 to 11, characterized characterized in that the organic solvent is a polar solvent. 13 · Clear solution according to claim 12, characterized that the organic solvent is N.N-dimethylacetamide or polyethylene glycol * . Clear solution according to one of the preceding claims, characterized in that they are used for Injection is suitable. -29-4 0 ο a 2 9/1 0 6 2 .- 29 - 15 · Clear solution according to one of the preceding. Expectations, characterized in that they Sulfonamide to the sulfonamide potentiator as base material in a ratio of 20: 1 to 0.1: 1 (w / w). 16. Clear solution according to claim 15, characterized that the ratio of sulfonamide to sulfonamide potentiator is about 5: 1. 17 · Clear solution according to one of the preceding claims, characterized in that it 1 to ■ Contains 4-0 weight pounds sulfonamide. 18. Clear solution according to claim 1? ·, Characterized in that it contains 10 to 30 wt. # SuIfon- contains amide. 19 · Clear solution according to one of the preceding claims, characterized in that they are 1 to 10 wt. 0, preferably 1 to 5 wt. # Sulfonamide potentiator, calculated as base material, contains. 20. Clear solution according to claim 1 essentially as described in any of the preceding examples. -30-4t) 9 8 2 9/106 2- Monosaureaddxtionssalz a pharmaceutically acceptable organic acid and a 2,4-diaminopyrimidine of the formula ₂ - / O V- 7 8 9
wherein the radicals R ', R and R ^{y are} identical or different and each alkyl or alkoxy group with 1 to 4- i'.ohlenjfetoff- ΓΊ O atoms or the radicals R 'and R together form an alkylenedioxy group with 1 to M carbon atoms, such as a methylenedioxy group. 22. monoaddition salt of an acid according to claim 21, characterized in that the 2,4-diaminopyrimidine Trimethoprim is. 23 · monoaddition salt of an acid according to claim 21 or 22, characterized in that the pharmaceutical compatible organic acid is citric acid. 409829/1062